A basic countermeasure to prevent recidivation of allergy is to avoid exposure to allergen. For example, in the case of food allergy, a countermeasure is taken by not eating allergen-containing food, refraining ingestion thereof or attenuating its allergenic property by thorough heating. In the case of pollen allergy, the most simple and effective countermeasure is to wear a mask or safety goggles or to refrain going out when drifting amount of pollen is large. These basic countermeasures are taken in daily life.
However, the object of these countermeasures is to prevent recidivation of allergic symptoms and not to perform fundamental treatment, although spontaneous remission may be expected in some cases.
In recent years, substitute milks for the mother's milk in which partially hydrolyzed peptide of milk protein is used as a nitrogen source have been put on the market to be used by familially allergic high risk babies for preventing crises of allergy. However, since there is no definite ground that the crises of milk allergy do not occur easily after changing to ordinary milk and dairy products, it is evident that these substitute milks are merely one of the choices to avoid antigens.
On the other hand, induction of the state of immunological tolerance is a therapeutic or preventive method in which its expected effects can be explained at least by its immunological mechanism. As examples of such a method, hyposensitization therapy and oral tolerance are known and have been carried out practically.
There are some reports in which percutaneous hyposensitization therapy is applied to treatments. Warner et al. disclose that a delayed asthmatic reaction induced by inhalant tick antigen was inhibited by hyposensitization therapy using a tick antigen preparation (Warner, J. O. et al., Lancet, 2:912 (1978)). Also, Norman et al. disclose that increase in the production of IgE antigen at a flowering time was inhibited by hyposensitization therapy using a urea-modified antigen IgE as a main antigen of ragweed pollen (Norman, P. S. et al., J. Allergy Clin. Immunol., 66:336 (1980)).
Patriarca et al. disclose oral hyposensitization therapy for treating food allergy (Patriarca, G. et al., eds., Food Allergy, Milano, Massom Italia, p.131 (1979)). Patriarca et al. have administered to patients who were allergic to milk, eggs or fruits, starting with a dose of 1 .mu.g which was gradually increased thereafter by a factor of 1.5 for each step and finally succeeded in administering 10 g. Shenassa et al. disclose hyposensitization therapy of patients of peanut allergy (Shenassa, M. M. et al., J. Allergy Clin. Immunol., 75:177 (1985)). In the case of food allergy, however, the cause of the disease is an antigen which passed through the same route to begin with, and serious symptoms frequently occur even by an extremely small amount of the antigen, so that it seems to be difficult to carry out the treatment using a specific oral hyposensitization therapy without causing an allergic reaction because of a danger at least when un-treated antigen is used.
Recently, oral immunological tolerance is drawing attention as an effective method for treating autoimmune patients. Trentham et al. disclose the case of treating patients suffering from chronic rheumatoid arthritis (Trentham, D. E. et al., Science, 261:1727 (1993)). When each patient was allowed to ingest 0.1 to 0.5 mg of fowl II type collagen for 90 days in a total amount of 33 mg, the rheumatic symptoms were attenuated and 4 of 28 cases have completely recovered from the disease. Also, Weiner et al. disclose the clinical results of patients suffering from multiple sclerosis (Weiner, H. L. et al., Science, 259:1321 (1993)). A bovine myelin antigen containing myelin basic protein was administered to the patients with a dose of 300 mg a day for one year. Although significant effect was not found as a whole, an effect was observed in certain groups.
A living custom of Indians (Dakin, R., Am. J. Med. Sci., 4:98, (1829)) and lacquer artisans in relation to the prevention of lacquer poisoning is well known as a prior art means for inducing immunological tolerance for the purpose of prevention. They have learned from their ancestors that children who were forced to eat lacquer would hardly be poisoned with lacquer later, and this is still handed down by tradition.
Wells et al. have studied and reported the phenomenon of oral immunological tolerance for the first time as a science (Wells, H. G. et al., J. Infect. Dis., 8:66 (1991)). Wells et al. disclose that, when un-sensitized guinea pigs are allowed to ingest ovalbumin, an anaphylactic reaction cannot be induced using the antigen. In Hanson et al., an aqueous solution of ovalbumin was administered to mice of a highly ovalbumin-responding line by single and plural gastric administration and then the mice were immunized with the same antigen by intraperitoneal injection using aluminum hydroxide gel as the adjuvant (Hanson, D. G. et al., J. Immunol., 123:2337 (1979)). Hanson et al. disclose that, as a result, the production of serum anti-ovalbumin antibodies and reagin antibodies was inhibited almost completely.
Antigens which induce oral immunological tolerance are not limited to food antigens. Aramaki et al. disclose that, when an extract of ragweed pollen was orally administered to mice and then the same antigen was used in booster together with an adjuvant, production of specific IgE antibodies was inhibited (Aramaki, Y. et al., Immunol. Lett., 40:21 (1994)). Ishii et al. disclose that, when guinea pigs were immunized with a tick extract by parenteral administration using aluminum hydroxide as an adjuvant and then the extract was orally administered for 1 week, an oral hyposensitization effect was observed, because threshold value of a tick inhalation induction test and threshold value of histamine inhalation were increased, thereby discussing that oral hyposensitization therapy would be effective also upon pollen allergy (Ishii, A. et al., Int. Arch. Allergy Appl. Immunol., 94:288 (1991)).
It is said that aptness to cause induction of oral immunization is different depending on kinds of animals. According to reports so far published, it is considered that ruminants, rabbits and guinea pigs are resistant to the induction, and rodents such as mice, rats and the like are sensitive to the induction. Even in the case of human, a possibility of establishing oral immunological tolerance has been suggested by Korenblatt et al. and Lowney (Korenblatt, P. E. et al., J. Allergy, 41:226 (1968); Lowney, E. D., J. Invest. Dermatol., 512:411 (1968)). Recently, Husby et al. have asked a volunteer to ingest 0.5 of hemocyanin of a shellfish, Macroschisma siensis, a protein which is not generally taken by human, and subcutaneous immunization was carried out thereafter, and suggested that immunological tolerance could be induced at least in T lymphocytes (Husby, S. et al., J. Immunol., 152:4663 (1994)).
In the above cases, all of the antigens are used in the form of aqueous solution as if a coincidence, but the reason for this is not described. Since comparison of these antigens with test groups in which other components are added is not described, it is evident that such an administration in the form of aqueous solution is not selected on purpose.
It is known in general that antigens having stronger property to induce immune response also have stronger property to induce immunological tolerance. Because of this, antigens to be used for the induction of the tolerance (tolerogens) are un-hydrolyzed in most cases. On the other hand, JP-A-5-5000 (the term "JP-A" as used herein means an "unexamined published Japanese patent application") and JP-A-7-101873 propose use of protein hydrolyzates for preventing crises of milk allergy. For example, in JP-A-5-5000, mice were provided with a solid feed preparation containing a peptide having a molecular weight of not more than 10,000 prepared by hydrolyzing casein or whey protein. Thereafter, each un-hydrolyzed sample of these proteins was intraperitoneally administered together with Freund's adjuvant to effect booster, thereby finding that production of specific antibodies was significantly low in comparison with the control group in which ion exchange water containing no peptide was provided. Since the antigenicity is reduced to a degree while maintaining the immunological tolerance function, it is concluded that these peptides having a molecular weight of not more than 10,000, namely partial protein hydrolyzates, are useful as food substances which can sufficiently activate the allergy defense mechanism.
However, the results in JP-A-5-5000 do not show that the tolerance induced by the pre-administration of the peptide prepared by partial protein hydrolysis is also effective in a case in which the original un-hydrolyzed protein is provided thereafter. The same can be said about the comparative group in which un-hydrolyzed protein was provided as the tolerance inducing antigen. To begin with, these results have a problem in that there is no comparative group in which the production of specific antibodies was said to be induced by continuous provision of un-hydrolyzed protein.
Although there are many reports on the use of percutaneous specific hyposensitization therapy as an effective symptomatic therapy of allergy (caused by food, pollen, ticks, house dust and the like), there is a danger of inducing shock and allergic symptoms such as asthma, fever and the like because of the injection of causal substances. Because of this, attempts have been made to inject these substances after attenuating their allergenic properties by polymerization, modification and the like, but complete avoidance of these actions have not been made.
Most serious problems of the percutaneous hyposensitization therapy are that the therapy requires a prolonged period of time which is at least several months and it gives pain in not a small degree. Accordingly, efforts for the treatment do not last long and are abandoned in the middle of the therapy in many cases. In addition, when it is prescribed as a therapy for children including babies, it causes emotionally difficult elements. Because of these factors, aside from the case in which it is used for the treatment of allergy, the percutaneous hyposensitization therapy is apt to be avoided when it is applied to the allergy prevention which has many uncertain elements, because its successive effects cannot be felt actually.
As a substitutive means for the percutaneous specific hyposensitization therapy having such problems, oral hyposensitization therapy is drawing attention in recent years. Since the oral hyposensitization therapy has an advantage of not causing pain of injection, it has been applied to the treatment of pollen and tick allergies, and its effects have also been recognized in a certain degree. In consequence, this therapy is expected to be useful for the fundamental prevention and treatment of various allergic diseases.
In the case of food allergy, however, the cause of disease is the ingested antigen in the first place, so that it is difficult to carry out the therapy using oral immunological tolerance without causing allergic reactions. Also, although there are many reports on animal experiments in which inhibitions of production of specific antibodies and delayed type reactions were observed and immunological tolerance was induced, the oral hyposensitization therapy still remains only as a possible candidate as a useful means to be applied to human because of the possible danger of establishing sensitization and inducing allergic symptoms.
The most important reason for the unstable effects of the oral hyposensitization therapy in the treatment of pollen and tick allergies and the hesitation in applying it to the prevention of the crises of food allergy is that nothing is known about a mechanism which decides selection of the completely incompatible phenomena of immunological tolerance and allergy induced by the ingested antigen.